It has been found that host responses to pathogens can be mediated via highly coordinated mechanisms involving both innate and adaptive limbs of the immune system. The innate immune system utilizes germline-encoded pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) that are distinct and unique to the pathogen. PRRs encompass a broad range of molecules that are secreted into the extracellular environment (e.g., collectins, ficolins, pentraxins, alarmins), exist in the cytosol (e.g., retinoic acid-inducible gene I-like receptors, and the nucleotide-binding domain and leucine-rich repeat-containing receptors), or are present on membranes.
Important among the transmembrane PRRs are the Toll-like receptors (TLRs), which are either expressed on the plasma membrane or in the endolysosomal compartments. At least 10 functional TLRs are encoded in the human genome, each with an extracellular domain having leucine-rich repeats (LRR) and a cytosolic domain called the Toll/IL-1 receptor (TIR) domain. The ligands for these receptors are highly conserved microbial molecules such as lipopolysaccharides (LPS) (recognized by TLR4), lipopeptides (TLR2 in combination with TLR1 or TLR6), flagellin (TLR5), single stranded RNA (TLR7 and TLR8), double stranded RNA (TLR3), CpG motif-containing DNA (recognized by TLR9), and profilin present on uropathogenic bacteria (TLR11). TLR1, -2, -4, -5, and -6 recognize extracellular stimuli, while TLR3, -7, -8 and -9 function within the endolysosomal compartment. The activation of TLRs by their cognate ligands leads to production of inflammatory cytokines, and up-regulation of major histocompatibility complex (MHC) molecules and co-stimulatory signals in antigen-presenting cells as well as activating natural killer (NK) cells (innate immune response), which lead to the priming and amplification of T-, and B-cell effector functions (adaptive immune responses).
The Type I interferon (IFN) family in humans includes approximately 20 IFN-α subtype genes in addition to individual genes encoding IFN-β, -κ, -ε and -ω; these monomeric secreted proteins bind to a single IFN-α/β receptor, which is constitutively expressed in virtually all cell types. Occupancy of TLR7 or TLR9 in antigen-presenting cells (APCs), particularly plasmacytoid dendritic cells (pDCs), leads to the induction of IFN-α/β. Although the Type I IFNs are best known historically for their antiviral activities, recent studies show that they have many essential functions in the control of adaptive immunity. First, Type I IFNs promote cross-priming through direct stimulation of DCs, leading to specific CD8+ lymphocytic responses to soluble antigens. Second, Type I IFNs potently enhance the primary antibody responses to soluble antigens, inducing sustained and durable humoral responses with appropriate isotype switching, as well as the induction of immunological memory. B lymphocytes can differentiate into two distinct types of functionally polarized effectors: B-effector-1-cells (Be-1), producing a Th-1-like cytokine pattern, or Be-2, characterized by a Th-2-like profile. It is of particular interest that recent reports suggest that IFN-α may serve as an initial trigger for Be-1-biased differentiation pattern. Third, Type I interferons secondarily induce Type II IFN (IFN-γ) secretion, also driving Th-1-biased adaptive immune responses. Type I IFN-inducing TLR ligands may, therefore, hold promise as vaccine adjuvants.